Systematic Review Protocol: Main Clinical Variables for the COVID-19 Patients’ Management at the Comprehensive Health Care in Brazil

Estael Luzia Coelho da Cruz-Cazarim¹, Pâmela Santos Azevedo², Adrielle Pereira Cordeiro³, Maiara Silva Araújo3, Damaris Salgueiro da Silva³, Matheus José Novais Landim³, Bárbara Caneschi da Costa³, Isadora Alhadas Oliveira Gomes³, Ana Karolina Toledo Fagundes³, Altacílio Aparecido Nunes⁴, Marina Morgado Garcia², Marcelo da Silva Silvério⁵, Alessandra Ésther de Mendonça⁵ & Maurilio de Souza Cazarim^5*

¹School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Brazil
²School of Pharmacy, Federal University of Minas Gerais, Brazil
³School of Pharmacy, Federal University of Juiz de Fora, Brazil
⁴Department of Social Medicine of Ribeirão Preto Medical School, University of Sao Paulo, Brazil
⁵Department of Pharmaceutical Sciences, School of Pharmacy, Federal University of Juiz de Fora, Brazil

*Correspondence to: Dr. Maurilio de Souza Cazarim, Department of Pharmaceutical Sciences, School of Pharmacy, Federal University of Juiz de Fora, Brazil.

Copyright © 2021 Dr. Maurilio de Souza Cazarim, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Systematic Review Justification
The epidemiological reach of COVID-19, emerging pandemic disease, has aroused concern among stakeholders worldwide for two main reasons: clinical and epidemiological information on the disease is still poor in evidence; and the influence of the health sector in the world economy, which has had a strong impact to the point of causing one of the biggest economic recessions in history [1,2]. It is estimated that more than 170 countries will experience a negative growth in per capita income in the year of 2020, with a 5,3% decline of the Gross Domestic Product in Brazil, which may reach 9,0% [1].

Clinical variables have been doubting object as its relevance and targeting for clinical management of COVID19. Factors related to treatment, co-morbidities, alternative therapies, can build important indicators for the fittest COVID19 care. Additionally, it is important to measure for comprehensive care in the health system and, thus to have the conception for different levels of care. In Brazil, these levels can be resumed in primary (preventive and basic care), secondary (specialized care), and tertiary care (hospital and clinicians for complex procedures) in the Public Health System [2].

In this sense, understanding the factors that influence the management of the disease, which have not yet been fully elucidated, and understanding their associations in the planning actions to cope with disease, can represent a reduction in the health systems overload and a more assertive path for the recovery of the population’s health. Fast actions and a proper management of patients infected with COVID-19 tend to soften economic impact, and this foster healthy feedback between the two sectors: health and economy [3].

Method
This protocol was registered at the base of PROSPERO - International Prospective Register of Systematic Reviews - for systematic review, number ID 256450 (https://www.crd.york.ac.uk/prospero/). Search strategy was performed to enhance methodological transparency and improve the reproducibility of the findings, following the PRISMA checklist [4]. Additionally, using the PICOS (Population/Intervention/ Comparison/Outcomes/Study Design) acronym we elaborated questions of systematic reviews, to ensure the systematic search of scientific literature.

As COVID-19 is an emerging disease, works/articles began to be published in January 2020, so the comparator and outcomes will not be considered in the search strategy, as it is a little-known topic, described in the literature, which does not influence the specificity of systematic review, but rather improve the sensitivity [5]. Studies was retrieved from four electronic bibliographic databases: MEDLINE via PubMed, Cochrane Library by Cochrane Central Register of Controlled Trials (CENTRAL), Excerpta Medica database (EMBASE) via Elsevier and Latin American and Caribbean Health Sciences Literature (LILACS). In addition, secondary searches in other sources, such as Google Scholar will be also carried out. The reference section of the included studies will be hand-searched for additional relevant studies. The search strategy will comprise only key terms according to PICOS acronym. The studies will be selected through the following order: reading the title, abstract and full text. The data will be tabulated to list the main variables of the patients affected by COVID-19 and, thus, extract the characteristics of the study, sociodemographic characteristics and description of the intervention and control groups, if any, as well as the analyzed indicators. To access the quality of the studies, the validated Downs and Black (1998) instrument will be used, which comprises a checklist of 28 items [6]. It allows to verify the general quality of the study, the internal and external validity, bias, confusion, and the power of the analyzes. This measurement is performed by a generated score and can be applied to observational studies [6], which is interesting due to the need addressed in this systematic review and the openness given by the journals to this pandemic for publication on this topic. The selection will be carried out with the aid of the Rayyan platform for systematic reviews [7].

The structuring of this systematic review, based on the Cochrane guide for systematic review and metaanalysis, progressing in the stages of search, selection, data extraction, compilation and analysis and results [5].

Review Question
What clinical variables are correlated to the clinical management of COVID-19 in primary care, secondary care and tertiary care?

Need for Systematic Review
A literature search will be carried out with the need to establish a pattern of the main influential variables for the epidemiological scenario of COVID-19, also meet a demand from the Brazilian Public Health System and generate synthesis of evidence [2].

Objective of the Review
The objective is to understand and relate qualitatively the different variables that have been associated with the clinical management of the COVID-19 for creating of a patient management algorithm in the public health system in Brazil.

Search and Review’s Strategy
The condition or the study domain will be defined for the management of COVID-19 developed in primary, secondary and tertiary health care. In addition, the treatments proposed, and respective clinical variables analyzed will be relevant to the domain of this themes [3].

The definition of research categories is based on two main categories for clinical trials (PICO) according to Higgins and Green (HIGGINS, GREEN, 2011) [7]. A summary of the Population (P), Interventions (I), Comparators (C) and Outcomes (O) considered, following the PICO acronym, is shown in table 1.

The Boolean operators to be used are: intra-category “OR” for word combination and, inter-category “AND” for word combination, population and intervention. No search filters will be used. It is emphasized that the search groups should be divided according to PIC, and when combining the “OR” the terms/words should always be in parentheses because unlinking the “OR” in the search may find off-target results and provide a broad, inaccurate search. Descriptors and keywords were extracted from controlled vocabularies, Emtree thesaurus for the strategies assembled in EMBASE, Health Science Descriptors (DeCS) in Portuguese/ Spanish/English for LILACS; MeSH (Medical Subject Headings) for PubMed, Cochrane e Scopus. The search was run on February 25th, 2021, in English, Portuguese and Spanish. The search strategies were adapted to each search base according to its peculiarities (Table 2).

Subtitle: MEDLINE, Medical Literature Analysis and Retrieval System Online; CENTRAL, Cochrane Central Register of Controlled Trials; EMBASE, Excerpta Medica Database; LILACS, Latin American and Caribbean Health Sciences Literature. For The LILACS, it must be used the DeCS and, of these descriptions/ keywords, the translation into the Portuguese and Spanish from the dictionary should be used when searching for words in the various fields.

The selected articles after reading the title and abstract will be fully analyzed to be included those studies that answer the question of the systematic review and that meet with the inclusion, exclusion, and eligibility criteria. Conflicts of article selection will be mutually resolved, when it is not agreed by the authors, a third researcher will have the decision-making power. In addition, original articles will be considered and limited to the languages english, spanish and portuguese. It should be noted that clinical trials will be analyzed in a separate group from other studies, and divided between randomized and non-randomized. Additionally, meta-analyses and systematic reviews will not be included in the results of the review, since this would require another course for the systematic review. The following inclusion and exclusion criteria are listed.

Inclusion Criterias
Studies with patients diagnosed with COVID-19 on pharmacological or non-pharmacological treatment for COVID-19 with the clinical management of COVID-19 at primary, secondary and tertiary levels of health care.

Exclusion Criterias
Studies that did not consider the treatment of patients diagnosed with COVID-19; studies that analyze variables that are not reproducible for interventions regarding the clinical management of COVID-19; studies that do not point out variables correlated to the care of the patient with COVID-19; the variables described in the clinical management do not have clarity regarding their correlation with the disease; studies of narrative or integrative reviews, dissertations or theses, editorials, news, comments, letters to the editor, abstracts published in proceedings of scientific journals or congresses, and guidelines; studies that do not contemplate the PICO strategy.

Condition or Domain Covered in the Study
It’s important to know that this review was divided into three systematic reviews. It is important to know about clinical variables that have influences on patients’ final outcomes. They must be summarized differently at primary, secondary and terciary cares. In this sense, the studies must bring results that show the association among clinical variables and outcomes for COVID-19 patients.

Measures of Effect
The effect will be measured by Relative Risks for experimental studies and odds ratio for observational studies reasoned in extracting those significant variables from selected studies in this review.

The eligibility of the studies found will be analyzed for the studies included in the review and will follow the criteria according the previously prepared checklist:

1. Evaluator’s name;

2. Study ID:

• Author, title and reference.

3. Eligibility requirements:

• Verification of all items described in the inclusion criterion;
• Biases that compromise the study due to potential conflicts of interest;
• Availability of data to be included in the systematic review.

4. Eligibility confirmation:

• Considering the course of the study, the intervention, the people involved, the study has potential to be included (The study’s course is stated and consistent with the methods);
• Participants consistent with the purpose of the study; Interventions considered are consistent with the study’s proposal;
• The evaluated results are consistent with the study’s proposal)? (Yes or No)

The data synthesis and tabulation will occur in such a way that the quantitative and qualitative data have been extracted from the studies included in the review using the data form developed by the reviewers (excel table template). After the end, the collaborators will assist in the discussion and interpretation of the analyzed data for the set of variables.

Risk of Bias Assessment (Quality Assessment):
Initially, the bias assessment will be performed using the Cochrane guideline of bias risk classification [5]. The risk of bias assessment will be evaluated for clinical trials and observational studies in order to access the quality of the study, Downs and Black instrument will be used, that makes up a 28-item checklist (allows to check the overall quality of the study, the internal and external validity, biases, confounding and power of the analyses).

Stage of Data Extraction

● Identification of clinical variables associated with the clinical course and management of COVID-19;

● Assemble the Excel spreadsheet with the categories of variables selected added in columns;

● Start the data extraction as:

o Fundamental variables:

1. Year
2. Reference
3. Country
4. Author
5. Planned sample number

o Details of the methods:

1. Type of study
2. Study design (how many groups; mode of data analysis)
3. Follow-up time
4. Randomization (“adequate”, “inadequate” or “not reported” by the study)
5. Confidential allocation (reported or unreported)
6. Blinding scheme:
• Investigators - “yes”, “no” or “not reported”
• Participants - “yes”, “no” or “not reported”
• Outcome evaluators - “yes”, “no” or “not reported”

o Participants:

1. Number of patients randomized by treatment mode or divided between comparison groups (exposed and unexposed)
2. Number of follow-up losses per group

o When clinical trials: clinical protocol

● Study phase
● Type of screening (inclusion criteria and sample planning)
● Assessment of safety and/or effectiveness
● Gold standard comparator (placebo or standard treatment? Which one?)
● Others.

o Health care level:

1. Primary or preventive
2. Emergency
3. Hospital: Outpatient
4. Hospital: Hospitalization
5. Hospital: ICU admission COVID-19

o Treatment

● Self-isolation only
● Basic medication + Self-isolation
● Basic medication + exams + hospitalization
● Oxygen therapy
● Intubation + sedation
● Renal Therapy
● High technological density procedures

o Outcomes

● Definition of each outcome investigated given the clinical condition of the study population;
● Unit of measure (if applicable) used as the gold standard (yes or no)
• Define death or survival
• Define disability or sequela criteria
• Perfect health, as before the disease

o For scales:
• report the upper and lower limits;
• report how high or low the score is and whether there has been clinical improvement

● Results

o For each outcome, report categorical and/or continuous and/or discrete variables.

o Calculate the rate of remission or recovery (control of clinical condition)

1. Sociodemographic descriptive data:

• Average age
• Percentage of sex
• Average income
• Education
• Ethnicity
• Previous disease history
• Comorbidities
• History of health events associated with CNCD

2. Clinical parameters of clinical interest:

• Staging the population’s risk
• Obesity
• Smoker
• Alcoholic
• Types of pre-existing diseases

Others

Note: Data referring to baseline characteristics of patients between studies summarize clinical heterogeneity. The difference between the comparative base of the study population can influence the extrapolation of the results. Thus, the protocol of this review provides for investigating which subgroups at each level of health care, including confounding factors that may contribute to the inconsistency of the findings: analyzing the difference in groups between the variables of age, sex, comorbidities, for example.

Analysis of the Results
Before the moment of consensus between the two researchers, the agreement between them will be analyzed by the Kappa coefficient, with a value above 0.80 being acceptable, otherwise, there will be a need to restructure a new search strategy. The Mann-Whitney test will be performed to test the difference between the quality scores of the studies with favorable and unfavorable clinical results. Other statistics will be used according to the behavior of the variables to be analyzed.

● Analysis of subgroups or subsets: The extraction of data for each level of care will be planned together, which will allow the listing of important subgroups or sets to be analyzed.

Main Outcome
Correlation degree of the clinical variable to the progression or remission of COVID-19.

● Primary outcomes
Correlation degree of the clinical variable to the progression or remission of COVID-19.

● Secondary outcomes
Patients’ features or co-variables associated with the progression or remission of COVID-19.

Bibliography

1. Lamucci, S. & globo Valor, O. (2020). FMI projeta retração de 5,3% para economia brasileira em 2020.
2. Opas - Organização Pan-Americana de Saúde (2020). Folha informativa - COVID-19 (doença causada pelo novo coronavírus). Brasília: Opas, 2020.
3. Brasil (2020). Ministério da Economia. Medidas do grupo de monitoramento dos impactos da COVID-19 pandemia.
4. Shamseer L., Moher D., Clarke M., Ghersi D., Liberati A., Petticrew M., et al. (2015). Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ., 349, g7647.
5. Downs, S. H. & Black, N. (1998). The feasibility of creating a checklist for the assessment of the methodological quality both of randomized and non-randomized studies of health care interventions. J Epidemiol Community Health., 8(52), 377-384.
6. Ouzzani, M., Hammady, H., Fedorowicz, Z., et al. (2016). Rayyan - a web and mobile app for systematic reviews. Systematic Reviews, 5(210).
7. Higgins, J. P. T. & Green, S. (2008). Cochrane Reviewers’ Handbook, Version 5.1: Cochrane Handbook for Systematic Reviews of Interventions. The Cochrane Collaboration, 2008.